Among its many peculiarities, the brain has one feature that conspires against the success of most modern oncological treatments: it lacks the cells that initiate immune responses (called “dendritic”). i.e, The brain may be the target of the immune response (as in the case of multiple sclerosis, which attacks the myelin, the protective covering of neurons, and causes communication problems between them), but can’t excite it,
Thinking about how to resolve this intersection that adds to the difficulties in treating certain brain tumors such as gliomas, Two Argentine researchers living in the United States, Pedro Lowenstein and María Castro, envisioned a simple alternative route., They decided to combine gene therapy (introducing an adenovirus with a gene that attracts dendritic cells in the brain) with immune-stimulating drugs to destroy the cells that could not be removed by surgery. And…Eureka! The results of the Phase 1 trial (in 18 patients) were promising. Furthermore, they open the door to continue exploring this strategy.
The black spot is the tumor, surrounded by an infiltrating area of malignant cells; Left side in rodents, right side in humans
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The work has just been published Lancet Oncology (DOI: 10.1016/s1470-2045(23)00347-9) And this is encouraging because Grade four gliomas, like the one studied by the Lowenstein-Castro couple who work at the University of Michigan, do not have a good prognosis., Its response to common treatments (chemotherapy and radiotherapy) is limited and typical survival is about 14 to 15 months.
,How does the immune response work? Basically, like neurological reflexes -Lowenstein explains in a telephone conversation from America. For example, if your knee is hit with a hammer, the signal travels to the spinal cord, where it travels from sensory neurons to motor neurons. He returns to the court and is kicked out. The immune system works the same way, only it is mediated by cells, not neurons. And the essential cells are the so-called dendritic cells, which take the antigen (a substance that triggers the production of antibodies), carry it through lymphatic vessels to the lymph nodes, present it to T cells, which begin to spread. And return. At the initial location where Noxa (the pathogen agent) was supposed to eliminate it. The problem is that there are no dendritic cells in the brain. The brain can be the target of immune attack as long as there is stimulation of the immune system in the periphery. so, What we thought: Given that what is missing in the brain are dendritic cells, how can we attract them? And we designed this treatment in which we used two adenoviruses. One that expresses a cytokine (small protein important for controlling the growth and activity of other cells of the immune system and blood cells) called Flt3L that will recruit dendritic cells from the central nervous system and direct them to the site of the tumor. will take. Active. The other contains (the enzyme) thymidine kinase (HSV-1-TK) which doesn’t do anything on its own, but when combined with a drug called Valtrex, if the cell divides, it stops DNA synthesis and kills it.
The treatment works in two stages: The virus with thymidine kinase plus valtrex kills the cells, and in doing so releases antigens and other factors that activate dendritic cells. These, already partially activated by Flt3L, stick to the antigen, leave the brain, travel to lymph nodes and promote the multiplication of T lymphocytes. Which are going to attack the tumor. “By expressing high amounts of Flt3L they attract dendritic cells that exist outside the brain,” Loewenstein highlights. We displayed all this in millions of newspapers between 1994 and 2023. Well, it’s not millions, but it feels like it…” he jokes.
In fact, the number of tasks is not small: about 50 were necessary to test each hypothesis step by step over a quarter of a century. “This is the first demonstration that two viruses are necessary for the therapy to work,” the scientists emphasize. When we treated laboratory mice with thymidine kinase alone, 80% died. When we do it with TK plus Flt3L, 75% survive. This is the first evidence that there is synergy between the two viruses and that it works through the immune system. That is, if someone removes the immune system, the therapy stops working.
Lowenstein and Castro were demonstrating the merits of this idea in animal models until several years ago, when one of the people in charge of evaluating their research project at the FDA in order to give them a subsidy challenged them to test it in humans. Had given.
“One interesting thing we showed is that when we injected an adenoviral vector into the brain it continued to express itself for a long time, more than a year,” he explains. This is slightly contrary to what is thought about adenovirus, as it is a virus that does not integrate into the genome. How can he survive so long? But we saw it. “So we are asking the FDA to be able to treat patients longer term with Valtrex.”
After the tumor is removed, the virus is injected during surgery. 20 injections are made into the surrounding area, which is infiltrated, which is usually where the recurrence is seen, an area of one to two centimeters that surrounds the cavity left by the glioma.,
“We had no toxicities that limited the dose of virus we used or other significant adverse effects, and patients lived an average of 21.3 months. Three lived more than three years; Five to one and he’s still alive – says Loewenstein -. With the immunohistochemistry assay, we observed that T cells increase, and we also demonstrated that some immune cells do so as well between the first and second surgeries. And what undoubtedly increases are dendritic cells. it means that We were able to show that both effector and dendritic T cells multiply, initiating the overall immune response.,
From now on, scientists are planning many tests. Among other things, they will test this approach in low-grade tumors, such as astrocytomas (which rarely metastasize). And also in child cancer.
Cells that express thyminokinase two years after injecting adenovirus (image generated by Marilu Varela)
,We are preparing for its implementation The same therapy is applied to children with malignant tumors -says Maria Castro-, which grow in the cerebral cortex and are also fatal. Since the results in adults were very good, and the expression of one of the transgenes lasted for many years, it means that we can give the drug to children for a long time and still get very good results. We believe that the combination (with other treatments) will be very powerful, because radiation stimulates the immune system through other mechanisms and induces programmed cell death. This process releases compounds that are powerful stimulants of innate immune cells. So the combination will be very, very powerful.
“We want TDK to kill tumor cells,” Lowenstein summarized. But for this you will need TDK, Valtrex and Cell to split. If any of these three fails (the cell was not infected, it did not divide, or there was no Valtrex), the therapy does not work. We now have evidence in humans that previously was only in animals: thymidine kinase is expressed up to two and a half years after patients are infected. This is completely unexpected! “I think this is a little gem of a trial, because it opens up the possibility that if we continue to administer Valtrex, we may continue to kill tumor cells.”
And Castro concluded: “Another important aspect is that this therapy can be used in countries that do not have very complex technology. The vector (virus) is frozen; That is, you only need a -80 °C freezer to store them. It will be very easy to implement in Argentina and the rest of the region, India and other countries,